The posterior ocular disease generally means a disease at the vitreous body, the retina, the choroid, the sclera or the optic nerve, and these diseases are deeply involved with neovascular expression or vascular permeability enhancement. That is, in the posterior ocular diseases such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, uveitis, etc., it has been known that neovascular expression or enhancement of vascular permeability is a main factor of formation of the pathological condition and progress of the pathological condition, so that it is useful for the treatment of these diseases to inhibit neovascularization, or to suppress vascular permeability enhancement (Non-Patent Document 1 and Non-Patent Document 2).
On the other hand, chemokine is a physiologically active protein which mainly acts on an immune system in vivo, and at present, substances exceeding 50 kinds have been revealed, which can be classified into four of C, CC, CXC, and CX3C based on the structural differences of the common cysteine in the amino acid sequence. The respective chemokines bind to GPCR (G protein-coupled receptor) and show their physiological actions, and in particular, the receptor to which MCP-1 being a CC chemokine binds, is called as CCR2.
In Non-Patent Document 3 and Non-Patent Document 4, there are disclosed that RS-504393 which is a CCR2 receptor antagonist has a protective effect onto nephropathy or endotoxin-induced pneumonopathy of diabetes model mouse.
Also, in Patent Document 1, there is disclosed that a tetrahydropyranylaminocyclopentylcarbonyltetrahydropyridopyridine derivative which controls an activity of a chemokine receptor such as a CCR2 receptor, etc., and synthetic examples of a plural number of tetrahydropyranylaminocyclopentylcarbonyltetrahydropyridopyridine derivatives are described. In addition, it has been disclosed that the tetrahydropyranylaminocyclopentylcarbonyltetrahydropyridopyridine derivative is useful for prophylaxis or treatment of inflammatory and immunoregulatory disorders and diseases, an allergic disease, atopic conditions (allergic rhinitis, dermatitis, conjunctivitis and asthma, etc.) and autoimmune diseases such as rheumatoid arthritis and atherosclerosis, etc.
Also, in Patent Document 2, ((1R,3S)-3-isopropyl-3-{[3-(trifluoromethyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl]carbonyl}cyclopentyl)[(3S,4S)-3-methoxytetrahydro-2H-pyran-4-yl]amine succinate which is one of the tetrahydropyranylaminocyclopentylcarbonyltetrahydropyridopyridine derivative has been disclosed, and shown to be a CCR2 receptor antagonist.
However, there is neither described nor suggested in Patent Documents 1 and 2, and Non-Patent Documents 1, 2, 3 and 4 about the effects exerted on the posterior ocular disease by the tetrahydropyranylaminocyclopentylcarbonyltetrahydropyridopyridine derivative, in particular, a compound represented by the formula (1):
its enantiomer or diastereomer, or their pharmaceutically acceptable salts.